Nitrosourea substituted phosphonates and pharmaceutical use

ABSTRACT

New nitrosourea compounds that can be used as medicaments and correspond to the general formula I ##STR1## in which R 1  is hydrogen, C 1  -C 6  alkyl or phenyl, 
     R 2  is hydrogen, C 1  -C 6  alkyl, thienyl, or phenyl which may carry substituents, 
     R 3  is hydrogen, C 1  -C 6  alkyl, or benzyl which may carry substituents, or 
     R 2  and R 3  together represent --(CH 2 ) m  --, m being 3 or 4. 
     Pharmaceutical compositions; therapeutic administration especially for the treatment of tumours.

The present invention relates to new nitrosourea compounds, process forthe preparation thereof and pharmaceutical compositions containing them.

It relates especially to nitrosourea compounds of the general formula I##STR2## in which R₁ represents a hydrogen atom, a straight-chain orbranched alkyl radical containing from 1 to 6 carbon atoms; or a phenylradical which may carry as substituent a halogen atom or an alkyl oralkoxy radical containing from 1 to 5 carbon atoms;

R₂ represents a hydrogen atom, a straight-chain or branched alkylradical containing from 1 to 6 carbon atoms and which may carry acarboxy or alkoxycarbonyl radical including from 2 to 6 carbon atoms; athienyl, phenyl or benzyl radical which may carry as substituent ahalogen atom or an alkyl or alkoxy radical each containing from 1 to 5carbon atoms;

R₃ represents a hydrogen atom, a straight-chain or branched alkylradical having from 1 to 6 carbon atoms, or a benzyl radical which maycarry as substituent a halogen atom or an alkyl or alkoxy radical eachhaving from 1 to 5 carbon atoms; or, alternatively,

R₂ and R₃ together represent a group --(CH₂)_(m) -- in which m has thevalue 3 or 4, in racemic form or in the form of optical isomers.

The subject of the present invention is also a process for thepreparation of compounds of the general formula I, characterised in thatan α-aminophosphonate compound of the general formula II ##STR3## inwhich R₁, R₂ and R₃ have the meanings defined above for the formula I,is condensed with an excess of β-chloroethyl isocyanate of the formulaIII

    Cl--CH.sub.2 --CH.sub.2 --N═C═O                    (III)

to give new compounds of the general formula IV R1 ? ##STR4## in whichR₁, R₂ and R₃ have the meanings defined above, and the nitroso group isintroduced into the compounds of the formula IV to give compounds of theformula I.

The condensation is preferably carried out in water or in a solventselected from the chlorinated solvents, such as, for example,chloroform. It is advantageous to operate at a temperature between 0°and 10° C., optionally in the presence of a mineral or organic base.

The introduction of the nitroso group into the new compounds (IV) toform nitrosoureas of the general formula I is carried out, for example,by the action of sodium nitrite in formic acid cooled to 5° C. or,alternatively, by nitrosyl chloride in a solvent, such as pyridine, forseveral hours at a temperature of 0° C., according to the methodsdescribed by J. L. MONTERO et al. in Eur. J. Med. Chem. 1981, 16, 539.

The starting materials of the general formula II are α-aminophosphonicacids or α-aminophosphonates which are already known in the literature;the main processes for the synthesis of these compounds have beendescribed by:

K. D. BERLIN, R. T. CLAUNCH and E. T. GAUDY in J. Org. Chem. 1968, 33,3090

J. KOWALIK and P. MASTALERZ in Synthesis 1981, 57

J. OLEKSYSZYN and R. TYKA in Tetrahedron Letters, 1977, 22, 2823, and

A. DEHNEL and G. LAVIELLE in Bull. Soc. Chim. Fr. 1978, 95.

All the new compounds forming part of this invention can be purified byphysical methods such as crystallisation or chromatography.

The present invention also relates to the optical isomers of thecompounds corresponding to the general formula I. These isomers may beprepared from optically active forms of the general formula II byresolution of the racemic compounds.

There may be mentioned as resolving agent, for example, (+) and (-)dibenzoyltartaric acids.

The compounds of the general formula I have interesting pharmacologicaland therapeutic properties. These compounds have an anti-bacterialactivity. In addition, the pharmacological properties of these compoundsmake them more interesting for the potential treatment of tumors thanthe nitrosoureas which are used as references and which have long beenrecognised as having oncolytic and oncostatic activities.

The compounds according to the invention are tested by their capacity toincrease the life-span of mice bearing tumorous cells inoculated byintraperitoneal or intramuscular route in accordance with the protocolsedicted by the National Cancer Institute (U.S.A.) and published by R. I.GERAN et al. in Cancer Chemotherapy Reports 1972, part III, Vol. 3 (2),1-87.

It was found that when administered by intraperitoneal route thecompounds according to the invention are capable of prolonging thelife-span of tumour-bearing mice at a dose of 1 mg/kg and above and ofinducing long-term survivors at a dose of 5 mg/kg as is the case for thecompound of example 4. Given per os, these compounds increase thelife-span of tumor-bearing animals. The rate of effectiveness of theactive doses per os over the active dose by intraperitoneal route isgreater for the compounds according to the invention than for thereference products (F. SPREAFICO et al. in Nitrosoureas: current statusand new developments, A. W. PRESTAYKO et al. editors, 1981, AcademicPress (New York); Experimental Evaluation of Antitumor Drugs in the USAand USSR and clinical correlations; National Cancer Institute MonographNo. 55; National Institutes of Health USA 1980).

The compounds according to the invention can slow down the developmentof tumor cells which have been inoculated intrathecally, thus provingtheir capacity to cross the blood-brain barrier. In the same way, thesecompounds are capable of inhibiting the growth of carcinomas graftedinto the muscle or under the skin of a mouse even when treatment onlybegins several days after the grafting.

The antimetastatic capacity of the compounds of the present invention ismeasured by the reduction, compared with untreated animals, in thenumber and weight of pulmonary metastases developed after intramuscularinoculation of carcinoma cells. The compounds according to the inventionreduce or prevent development of the metastases, for example compoundNo. 4 prevents the formation of metastases when it is administered at adose of 10 mg/kg as a curative treatment for 9 days.

The haemotopoietic toxicity is assessed, in animals treated with one orseveral administrations of the compounds according to the invention, bythe count of the peripheral blood cells and of the bone marrow, and thestem cells contained in the bone marrow (J. E. TILL and E. A. McCULLOCH,1961, Radiation Res., 14, 213). The nadir of cellular concentrationsthus calculated is noted 3 days after the start of treatment. The extentof this decrease is measured after treatment with one dose ofN-N'-bis(2-chloroethyl)-N-nitrosourea ("BCNU")-compound used as areference (W. C. TANG and G. EISENBRAND, Arch. Pharm. 1981, 314,910)--known to be the most effective against cancerous tumours, and withdoses of compounds according to the invention having the same beneficialtherapeutic effect. The recovery of the normal blood cell compositionoccurs on the tenth day after the start of treatment by the compounds ofthe invention, i.e. more rapidly than after administration of 25 mg/kgof BCNU. Moreover, the new compounds display less toxic side effects onthe bone marrow renewing cells.

The hepatic toxicity is assessed according to Wroblewski's method bymeasuring the pyruvic glutamic transaminase activity contained in theserum from Long Evans rats treated with an intraperitoneal injection of25 mg/kg of BCNU or with equipotential doses of the compounds accordingto the invention. Unlike BCNU, the products according to the inventiondo not show a notable hepatic toxicity. For example, treatment with 25mg/kg of compound No. 4 does not lead to an increase in the enzyme leveloutside the range usually found in untreated rats.

The compounds according to the invention are used in oral or parentaltreatment of animals for the alleviation or mitigation of tumors whichare responsive to treatment therewith.

The present invention also relates to pharmaceutical compositions usefulfor such antineoplastic therapy containing as active ingredient aderivative of the general formula I in admixture or in association witha pharmaceutically suitable excipient.

The pharmaceutical compositions so obtained are advantageously presentedin various forms such as, for example, tablets, dragees, soft gelatinecapsules, glossettes or galenic preparations suitable for sublingualadministration, suppositories or solutions for injecting or drinking.

The following examples, which are not limiting, illustrate theinvention. Unless otherwise stated, the melting points were determinedon a Kofler heating block.

EXAMPLE 1 1-[N-(2-chloroethyl)-N-nitrosoureido]-ethylphosphonic acid

(a) Preparation of 1-[N-(2-chloroethyl)ureido]ethylphosphonic acid

32 ml of a 1N sodium hydroxide solution is added to a solution of 2 g ofα-aminoethylphosphonic acid in 20 ml of water, the reaction medium beingcooled to 0° C. An equivalent (1.4 ml) of chloroethyl isocyanate is thenadded, still at the same temperature. After the addition, stirring iscarried out for approximately 30 minutes at ambient temperature. Afurther equivalent of β-chloroethyl isocyanate (1.4 ml) is added andstirring is maintained for a further 2 hours. When stirring iscompleted, the precipitate formed during the reaction is separated byfiltration and the aqueous solution is poured onto 30 ml of resin AG 50W-X4, recovered and evaporated to dryness. The residue is partiallydissolved in a few milliliters of boiling ethyl alcohol, then filteredhot to give 0.3 g of starting material which has not reacted. Afterevaporation of the ethanol, the residue obtained is recrystallised inwater. Yield: 54%; m.p.=180° C.

Analysis: Calculated: C, 26.03; H, 5.21; N, 12.15; Cl, 15.40. Found: C,26.32; H, 5.22; N, 12.20; Cl, 15.14.

(b) Preparation of 1-[N-(2-chloroethyl)-N-nitrosoureido]-ethylphosphonicacid

A solution containing 1 g of the1-[N-(2-chloroethyl)ureido]ethylphosphonic acid obtained above in 20 mlof formic acid is cooled to 0° C. 1 g of sodium nitrite is then added insmall portions and after stirring has been carried out for 30 minutesthe solution is diluted with 100 ml of water. The solution is passedover 40 ml of resin AG 50 W-X4, then evaporated in vacuo withoutexceeding a temperature of 30° C. The yellow oil obtained (1 g) isslightly unstable and is not further purified. It is identified as1-[N-(2-chloroethyl)-N-nitrosoureido]ethylphosphonic acid by customaryphysical methods (NMR; IR: see table).

EXAMPLE 2 α-[N-(2-chloroethyl)-N-nitrosoureido]-benzylphosphonic acid

α-[N-(2-chloroethyl)ureido]benzylphosphonic acid is prepared by theaction of β-chloroethyl isocyanate and α-aminobenzylphosphonic acidaccording to the method described in Example 1a. Yield: 75%; m.p.=195°C.

Analysis: Calculated: C, 49.33; H, 5.87; N, 10.28; Cl, 8.69. Found: C,49.03; H, 5.70; N, 10.26; Cl, 8.22.

The α-[N-(2-chloroethyl)-N-nitrosoureido]benzylphosphonic acid isobtained according to Example 1b by the action of sodium nitrite on theabove acid urea. Yield: 56%, slightly unstable yellow oil. Physicaldata: see table.

EXAMPLE 3 α-[N-(2-chloroethyl)-N-nitrosoureido]-benzylphosphonic aciddiethyl ester

(a) Preparation of α-[N-(2-chloroethyl)ureido]benzylphosphonic aciddiethyl ester

A solution of 0.05 mol of α-aminobenzylphosphonic acid diethyl ester in30 ml of chloroform is cooled to 0° C. in an ice-bath and then a largeexcess (0.06 mol) of β-chloroethyl isocyanate is added. The temperatureof the reaction is then maintained at 10° C. while continuing stirringuntil the reaction is complete. (Examination by thin layerchromatography is used to ascertain that the starting aminophosphonatehas disappeared completely. After evaporation of the solvent underreduced pressure, the crystalline residue is taken up in ether andfiltered, yielding 14.8 g of crystals. Yield: 85%; m.p.=82° C.

(b) Preparation ofα-[N-(2-chloroethyl)-N-nitrosoureido]-benzylphosphonic acid diethylester

The urea obtained above (0.02 mol) is dissolved in 60 ml of formic acidand cooled to 5° C. Over a period of 1 hour, an excess of sodium nitrite(0.08 mol) is then added in small portions.

After evaporation of the formic acid in vacuo at a temperature of lessthan 35° C., the residue is taken up in 200 ml of dichloromethane, thenwashed 3 times with 100 ml of distilled water. The organic phase is thendried over sodium sulphate, filtered and evaporated under reducedpressure, leaving 5.5 g of an oil which is then chromatographedaccording to the technique described by W. C. STILL in J. Org. Chem.1978, 43, 2923 using a mixture of CH₂ Cl₂ /MeOH (99/1) as eluant. Theoil so obtained (4.7 g) crystallises in isopropyl ether, yieldingcrystals melting at 95° C. Yield: 62%.

EXAMPLES 4 TO 16

The following compounds were prepared according to the process describedin Example 3:

(4) 1-[N-(2-chloroethyl)-N-nitrosoureido]ethylphosphonic acid diethylester: Yield: 52%; m.p.=85° C.

(5) α-[N-(2-chloroethyl)-N-nitrosoureido]-(4-chlorobenzyl)-phosphonicacid diethyl ester: Yield: 68%; m.p.=95° C.

(6) α-[N-(2-chloroethyl)-N-nitrosoureido]-(4-fluorobenzyl)phosphonicacid diethyl ester: Yield: 74%; m.p.=95° C.

(7) 1-[N-(2-chloroethyl)-N-nitrosoureido]-2-methylpropylphosphonic aciddiethyl ester: Yield: 68%.

(8) 1-[N-(2-chloroethyl)-N-nitrosoureido]butylphosphonic acid diethylester: Yield: 58%.

(9)1-[N-(2-chloroethyl)-N-nitrosoureido]-2-(4-methoxyphenyl)ethylphosphonicacid diethyl ester: Yield: 52%; m.p.=98° C.

(10) 1-[N-(2-chloroethyl)-N-nitrosoureido]-2-phenylethylphosphonic aciddiethyl ester: Yield: 46%; m.p.=68° C.

(11) 2-{1-[N-(2-chloroethyl)-N-nitrosoureido]pyrrolidinyl}-phosphonicacid diethyl ester: Yield: 48%.

(12)1-[N-(2-chloroethyl)-N-nitrosoureido]-2-(2-chlorophenyl)ethylphosphonicacid diethyl ester: Yield: 62%; m.p.=108° C.

(13) [N-(2-chloroethyl)-N-nitrosoureido]-(2-thienyl)methylphosphonicacid diethyl ester: Yield: 35%; m.p.=70° C.

(14) α-[N-(2-chloroethyl)-N-nitrosoureido]benzylphosphonic acid diethylester, laevorotatory isomer of Example 3: Yield: 35%; α_(D) ²² =-34.4°(c=2; CHCl₃).

(15) α-[N-(2-chloroethyl)-N-nitrosoureido]benzylphosphonic acid diethylester, dextrorotatory isomer of Example 3: Yield: 43%; α_(D) ²² =+36°(c=2; CHCl₃).

(16) [N-(2-chloroethyl)-N-nitroso-N'-benzylureido]methylphosphonic aciddiethyl ester. The starting[N-(2-chloroethyl)-N'-benzylureido]methylphosphonic acid diethyl esteris prepared according to the process described in Example 1.

The introduction of the nitroso group into the above urea is carried outusing nitrosyl chloride according to the following method: 0.02 mol ofthe urea obtained according to the process described in Example 1 isdissolved in dichloromethane and, after cooling to -10° C., first 7 mlof nitrosyl chloride and then 15 ml of pyridine are added. Afterstirring for 2 hours at 0° C., the reaction mixture is poured into 250ml of ice-water and then extracted using 3 portions of 100 ml ofdichloromethane. The combined organic phases are first washed with 2portions of 50 ml of 5% hydrochloric acid and finally with water. Afterdrying over sodium sulphate, the organic phase is evaporated underreduced pressure and 7 g of an oil are obtained which is chromatographedusing a mixture of chloroform/ethyl acetate (95/5) as eluant. Yield:70%.

(17) 1-[N-(2-chloroethyl)-N-nitrosoureido]ethylphosphonic acid diphenylester: Yield: 80%; m.p.=84° C.

(18) 1-[N-(2-chloroethyl)-N-nitrosoureido]ethylphosphonic aciddi(2-methoxyphenyl)ester: Yield: 85%; m.p.=83° C.

(19) 1-[N-(2-chloroethyl)-N-nitrosoureido]2-carboxyethylphosphonic aciddiethyl ester: Yield: 72%; m.p.=90° C.

(20) 1-[N-(2-chloroethyl)-N-nitrosoureido]2-ethoxycarbonylethylphosphonic acid diethyl ester: Yield: 80%; m.p.=103° C.

The physical characteristics of the intermediates of the general formulaIV are described in the following Table I ##STR5##

                                      TABLE I                                     __________________________________________________________________________                              Yld                                                                              MP  I.R. (cm.sup.-1)                             R.sub.1                                                                             R.sub.2     R.sub.3 %  (°C.)                                                                      ν(NH)                                                                          ν(CO)                                                                           NMR                                 __________________________________________________________________________    C.sub.2 H.sub.5                                                                                 H       80  82 3380 3250                                                                         1665 1550                                                                          1.05, .sub.-t,3H: 1.35,                                                       .sub.-t,3H; 3.50,m,4H; 3.80,                                                  -q,2H; 4.30, -q,2H; (J.sub.PH =                                               7Hz) 5.50, --dd,1H (J.sub.PH =                                                23Hz; J.sub.HH = 10Hz) H                                                      exchangeable:6.50, .sub.--m,1H;                                               7.50, .sub.--m,1H; 7.50,                                                      .sub.--,5H Ar                       C.sub.2 H.sub.5                                                                     CH.sub.3    H       85 <50 3200                                                                              1650-                                                                              1.10 to 1.70, .sub.--m,9H;                                           3400                                                                              1690 3.60, .sub.--m,4H; 3.90 to                                                    4.60, .sub.--m,5H                                                        1550 2H exchangeable ˜ 6.60        C.sub.2 H.sub.5                                                                      ##STR6##   H       70 122 3370 3290                                                                         1680 1550                                                                          1.00,.sub.-t,3H;                                                              1.50, .sub.-t,3H; 3.50,                                                       .sub.--m,4H; 3.70 to 4.60,                                                    .sub.--m,4H; 5.50, -d,1H; 6.45,                                               .sub.-s,1H exchangeable 6.40 to                                               7.70, .sub.--m,5H of which 1H                                                 exchangeable.                       C.sub.2 H.sub.5                                                                      ##STR7##   H       95 105 3300 3360                                                                         1685 1550                                                                          1.00, .sub.-t,3H; 1.50,                                                       .sub.-t,3H; 3.50, .sub.--m,4H;                                                3.60 to 4.50, .sub.--m,4H 5.50,                                               -d,1H; 6.40, .sub.-s,1H                                                       exchangeable 6.80 to 7.70,                                                    .sub.--m,5H                         C.sub.2 H.sub.5                                                                      ##STR8##   H       96 115 3350                                                                              1680 1550                                                                          0.90 to 1.60, .sub. --m,12H;                                                  1.70 to 2.50, .sub.--m,1H;                                                    3.60, .sub.--m,4H; 3.80 to                                                    4.60, .sub.--m,5H; 6.60,                                                      .sub.--,2H exchangeable             C.sub.2 H.sub.5                                                                     CH.sub.3(CH.sub.2).sub.2                                                                  H       88 --  3350                                                                              1680 0.70 to 1.70, .sub.--m,13H;                                              1550 3.50, .sub.--m,4H;                                                            3.80 to 4.30, .sub.--m,5H                                                     6.20 to 6.50, .sub.--m,2H                                                     exchangeable                        C.sub.2 H.sub.5                                                                      ##STR9##   H       82 --           1.30, .sub.-t,6H; 2.70 to 3.00,                                               .sub.--m,3H; 3.40, .sub.--m,4H;                                               3.60, .sub.-s,3H; 6.20,                                                       .sub.-s,1H exchangeable; 6.50,                                                -,1H exchangeable; 6.60 to                                                    7.10; spectr. AB,4H                 C.sub.2 H.sub.5                                                                      ##STR10##  H       92 105          1.20, .sub.-t,6H; 2.70 to 3.10,                                               .sub.--m,3H; 3.40, .sub.--m,4H;                                               3.80 to 4.20, .sub.--m,4H 6.20,                                               .sub.-s,1H exchangeable; 6.50,                                                -,1H exchangeable; 7.10,                                                      .sub.-s,5H Ar                       C.sub.2 H.sub.5                                                                     (CH.sub.2).sub.3    95 --  3320                                                                              1640 1.30, .sub.-t,6H; 1.70 to 2.30,                                               .sub.--m,4H;                                                             1535 3.20 to 3.60, .sub.--m,6H                                                     3.70 to 4.30, .sub.--m,5H                                                     6.50, .sub.-s,1H exchangeable       C.sub.2 H.sub.5                                                                      ##STR11##  H       86  97                                              C.sub.2 H.sub.5                                                                      ##STR12##  H       95  64          1.00 to 1.40, .sub.--m,6H;                                                    3.45, .sub.--m,4H; 3.80 to                                                    4.30, .sub.--m,4H; 5.65,                                                      --dd,1H; 6.40, .sub.-s,1H                                                     exchangeable; 6.70 to 7.20,                                                   .sub.--m,4H.                        C.sub.2 H.sub.5   H       90 --  C = 2 ethanol: Rotatory power                                                 α.sub.D.sup.22 = +9.5°                                           For other characteristics see 1st                                             example                                                                       of Table I                                   C.sub.2 H.sub.5   H       90 --  C = 2 ethanol: Rotatory power                                                 α.sub.D.sup.22 = -9.3°                                           For other characteristics see 1st                                             example                                                                       of Table I                                   C.sub.2 H.sub.5                                                                     H                                                                                          ##STR13##                                                                            85  64 3310                                                                              1640 1540                                                                          1.30, .sub.-t,6H; 3.40 to 3.60,                                               .sub.--m,6H; 3.80 to 4.30,                                                    .sub.--m,4H; 4.50, .sub.-s,2H;                                                5.80, .sub.-s,1H exchangeable;                                                7.20, .sub.-s,5H                     ##STR14##                                                                          CH.sub.3    H       82  98 3340                                                                              1690 1555                                                                          1.30, --dd,3H (J.sub.PH =                                                     17H.sub.3, J.sub.HH = 6.7Hg                                                   3.30, .sub.--m,4H; 4.20 to                                                    4.70, .sub.--m,1H; 5.80,                                                      .sub.-s,1H exchangeable; 6.15,                                                -,1H exchangeable; 6.80 to                                                    7.20, .sub.--m,10H.                  ##STR15##                                                                          CH.sub.3    H       86              1.30, --dd,3H;                                                                3.30, .sub.-s,4H; 3.50,                                                       .sub.-s,3H; 3.60, .sub.-s,3H;                                                 4.20 to 4.80, .sub.--m,1H; 5.80                                               to 6.30, .sub.--m,2H                                                          exchangeable. 6.50 to 7.10,                                                   .sub.--m,8H.                        C.sub.2 H.sub.5                                                                     CH.sub.2 COOC.sub.2 H.sub.5                                                               H       70  67 3380                                                                              ester                                                                              1.10 to 1.50, .sub.--m,9H; 2.50                                               to 2.70, .sub.--m,2H;                                                3440                                                                              1740 3.50, .sub.--m,4H; 3.80 to                                                    4.20, .sub.--m,6H;                                                       I. 1630                                                                            4.20 to 4.90, .sub.--m,1H; 6.30                                               to 6.50, .sub.--m,2H                                                     II. 1570                                                                           exchangeable.                       C.sub.2 H.sub.5                                                                     CH.sub.2 COOH                                                                             H       55 144 3260                                                                              1720 1.20 to 1.40, .sub.-t,6H; 2.30                                                to 2.70, .sub.--m,2H                                                 3360                                                                              1630 3.30 to 3.80, .sub.--m,4H; 3.80                                               to 4.50, .sub.--m,4H;                                                    1570 4.00 to 5.00, .sub.--m,1H;                                                    Spectrum carried out in D.sub.2                                               O + DM.sub.50.                      __________________________________________________________________________

The physical characteristics of the general formula I are described inthe following Table II ##STR16##

                                      TABLE II                                    __________________________________________________________________________                                  I.R. (cm.sup.-1)                                EX R.sub.1                                                                              R.sub.2     R.sub.3 ν(NH)                                                                          ν(CO)                                                                          NMR                                     __________________________________________________________________________    1  H      CH.sub.3    H               1.10 to 1.50, --dd (J.sub.PH =                                                15.4Hz, J.sub.HH = 7Hz),3H;                                                   3.50, .sub.-t, (J = 6Hz),2H; 4.10,                                            .sub.-t,2H; 3.70 to                                                           4.30, .sub.--m,1H                       2  H                                                                                                H               3.40, .sub.-t,2H; 3.95, .sub.-t,2H;                                           5.10, -d, (J.sub.PH = 20Hz),1H;                                               7.20, .sub.--m,5H.                      3  C.sub.2 H.sub.5                                                                       ##STR17##  H       3180                                                                              1720                                                                              1.10, .sub.-t,3H; 1.25, .sub.-t,3H;                                           3.45, .sub.--m,2H; 3.70 to 4.50,                                              .sub.--m, 6H; 5.55, --dd, (J.sub.PH                                           = 21Hz and J.sub.HH =  9Hz), 1H;                                              6.90 to 8.10, .sub.--m,6H.              4  C.sub.2 H.sub.5                                                                      CH.sub.3    H       3220                                                                              1720                                                                              1.20 to 1.80,9H; 3.40 to 3.70,                                                .sub.--m,2H; 3.90                                                             to 5.00, .sub.--m,5H; 7.40,                                                   .sub.--m,1H exchangeable                5  C.sub.2 H.sub.5                                                                       ##STR18##  H       3180                                                                              1710                                                                              1.20, .sub.--m,6H;                                                            3.45, .sub.-t,2H; 3.70 to 4.40,                                               .sub.--m,6H; 5.50, --dd,1H; 7.40,                                             .sub.-s,4H; 7.80, .sub.--m,1H                                                 exchangeable.                           6  C.sub.2 H.sub.5                                                                       ##STR19##  H       3180                                                                              1715                                                                              1.00 to 1.50, .sub.--m,6H; 3.30 to                                            4.40, .sub.--m,8H; 5.50, .sub.--m,1H                                          ; 6.90 to 8.00, .sub.--m,5H.            7  C.sub.2 H.sub.5                                                                       ##STR20##  H       3220                                                                              1720                                                                              1.00 to 1.50, .sub.--m,12H; 1.90 to                                           2.60,  .sub.--m,1H; 3.50, .sub.-t,2H                                          ; 3.90 to 4.70, .sub.--m,5H; 7.20,                                            .sub.--m,1H exchangeable.               8  C.sub.2 H.sub.5                                                                      (CH.sub.2).sub.2CH.sub.3                                                                          3220                                                                              1720                                                                              0.90 to 2.10, .sub.--m,13H; 3.50,                                             .sub.-t,2H;                                                                   3.90 to 4.50, .sub.--m,6H; 4.50 to                                            5.00, .sub.--m,1H                                                             7.30, .sub.--m,1H exchangeable.         9  C.sub.2 H.sub.5                                                                       ##STR21##  H       3230                                                                              1710                                                                              1.10, .sub.-t,3H; 1.50, .sub.-t,3H;                                           2.80 to 3.50, .sub.--m,4H 3.90 to                                             4.50, .sub.--m,6H;                                                            3.75, .sub.-s,3H; 4.50 to 5.00,                                               .sub.--m,1H; 6.70 to                                                          7.30, .sub.--m,4H; 7.40, .sub.--m,1H                                           exchangeable.                          10 C.sub.2 H.sub.5                                                                       ##STR22##  H       3240                                                                              1720                                                                              1.10,  .sub.-t,3H;                                                            1.50, .sub.-t,3H; 3.00 to 3.50,                                               .sub.--m,4H 3.90 to                                                           4.50, .sub.--m,6H; 4.50 to 5.00,                                              .sub.--m,1H; 7.30, .sub.-s,5H;                                                7.60, .sub.--m,1H exchangeable.                   .THorizBrace.                                                       11 C.sub.2 H.sub.5                                                                      (CH.sub.2).sub.3    --  1690                                                                              1.10 to 1.50, .sub.--m,6H; 1.80 to                                            2.70, .sub.--m,4H;                                                            3.40 to 4.00, .sub.--m,4H; 4.00 to                                            4.50, .sub.--m,6H;                                                            4.80, .sub.--m,1H.                      12 C.sub.2 H.sub.5                                                                       ##STR23##  H       3240                                                                              1725                                                                              1.20 to 1.60, .sub.--m,6H; 3.00 to                                            3.50, .sub.--m,4H; 3.50 to 4.50,                                              .sub.--m,6H; 4.50 to                                                          5.20, .sub.--m,1H; 7.00 to 7.50,                                              .sub.--m,4H; 7.50, .sub.--m,1H                                                exchangeable.                           13 C.sub.2 H.sub.5                                                                       ##STR24##  H       3170                                                                              1720                                                                              1.00 to 1.50,2 .sub.-t,6H; 3.40 to                                            3.60, .sub.-t,2H; 3.90 to 4.50,                                               .sub.--m,6H; 6.90 to                                                          7.50, .sub.--m,3H; 7.60 to 7.90,                                              .sub.--m,1H exchangeable.               14 C.sub.2 H.sub.5                                                                       ##STR25##  H       Laevorotatory isomer                                                                  α.sub.D.sup.22                                                          = -34,4° (C = 2; CHCl.sub.3)                                           .R. and NMR idem Example 2              15 C.sub.2 H.sub.5                                                                       ##STR26##  H       Dextrorotatory isomer                                                                 α.sub.D.sup.22 = +36°                                            C. (C = 2; CHCl.sub.3) I.R. and NMR                                           idem Example 3                          16 C.sub.2 H.sub.5                                                                      H                                                                                          ##STR27##  1690                                                                              1.20, .sub.-t,3H; 1.40, .sub.-t,3H;                                           3.30 to 4.50, .sub.--m,10H; 4.90,                                             .sub.-s,2H; 7.40, .sub.-s,5H.           17 C.sub.6 H.sub.5                                                                      CH.sub.3    H       3220                                                                              1710                                                                              1.60, --dd, (J.sub.PH = 17z,                                                  J.sub.HH = 7Hz),3H;                                                           3.35, .sub.-t,(J.sub.HH = 6Hz),2H;                                            4.400, .sub.-t,(J = 6Hz),2H;                                                  4.75, .sub.--m,1H;                                                            7.00, .sub.-s,10H; 7.35, -d,1H                                                exchangeable                            18                                                                                ##STR28##                                                                           CH.sub.3    H       3380                                                                              1730                                                                              1.40 to 1.90, --dd,3H; 3.30 to                                                3.60, .sub.-t,2H; 3.80,2 .sub.-s,6H;                                           4.00 to 4.30, .sub.1-t,2H; 4.50 to                                           5.50, 5 .sub.--m,1H; 6.80 to 7.40,                                            .sub.--m,8H; 8.00, .sub.-s,1H                                                 exchangeable.                           19 C.sub.2 H.sub.5                                                                       CH.sub.2 COOC.sub.2 H.sub.5                                                              H       3240                                                                              1740                                                                              1.10 to 1.50, .sub.--m,9H; 2.70 to                                            3.10, .sub.--m,2H;                                                        1720                                                                              3.40 to 3.70, .sub.--m,2H; 3.90 to                                            4.50, .sub.--m,6H;                                                        1520                                                                              4.50 to 5.50, .sub.--m,1H; 7.70 to                                            7.80, .sub.-s,1H exchangeable.          20 C.sub.2 H.sub.5                                                                      CH.sub.2 COOH                                                                             H       3280                                                                              1700                                                                              1.30 to 1.60,2 .sub.-t,6H; 2.80 to                                            3.30, .sub.--m,2H;                                                        1710                                                                              3.40 to 3.60, .sub.--m,2H; 4.00 to                                            4.60, .sub.--m,4H;                                                        1535                                                                              4.50 to 5.50, .sub.--m,1H.              __________________________________________________________________________

We claim:
 1. Nitrosourea compound corresponding to the formula I##STR29## in which R₁ represents hydrogen, alkyl having 1 to 6 carbonatoms or phenyl,R₂ represents hydrogen, alkyl containing 1 to 6 carbonatoms, and which may carry a carboxy or alkoxycarbonyl radical including2 to 6 carbon atoms; a thienyl, phenyl or benzyl radical which may carrya halogen atom or an alkyl or alkoxy radical containing 1 to 5 carbonatoms; R₃ represents hydrogen, alkyl having 1 to 6 carbon atoms; orbenzyl which may carry a halogen atom or an alkyl or alkoxy radicalhaving 1 to 5 carbon atoms; or, alternatively, R₂ and R₃ togetherrepresent a group --(CH₂)_(m) -- in which m has the value 3 or 4, inracemic form or in the form of optical isomers.
 2. A compound of claim 1which is α-[N-(2-chloroethyl)-N-nitrosoureido]benzyl-phosphonic aciddiethyl ester.
 3. A compound of claim 1 which is1-[N-(2-chloroethyl)-N-nitrosoureido]ethyl-phosphonic acid diethylester.
 4. A compound of claim 1 which is1-[N-(2-chloroethyl)-N-nitrosoureido]ethyl-phosphonic acid diphenylester.
 5. A compound of claim 1 which is1-[N-(2-chloroethyl)-N-nitrosoureido]2-ethoxy-carbonylethylphosphonicacid diethyl ester.
 6. Pharmaceutical composition for alleviating tumorssusceptible thereto containing as active ingredient a compound accordingto any one of claims 1 to 5 in association or admixture with anexcipient or an inert, pharmaceutically acceptable non-toxic carrier. 7.A method for treating a living animal body afflicted with a tumorresponsive to such treatment, comprising the step of administering tothe said living animal body having said tumor an amount of a compound ofclaim 1 which is effective for the alleviation of the said condition.